Peggy Sextius, Emilie Warrick, Amélie Prévot-Guéguiniat, Guillaume Lereaux, Florence Boirre, Ludwig Baux, Safa Ben Hassine, Jie Qiu, Xiaoming Huang, Jinzhu Xu, Sébastien Grégoire, Shosuke Ito, Kazumasa Wakamatsu, Xavier Marat
Research on new ingredients that can prevent excessive melanin production in the skin while considering efficacy, safety but also environmental impact is of great importance to significantly improve the profile of existing actives on the market and avoid undesirable side effects. Here, the discovery of an innovative technology for the management of hyperpigmentation is described. High-throughput screening tests on a wide chemical diversity of molecules and in silico predictive methodologies were essential to design an original thiopyridinone backbone and select 2-mercaptonicotinoyl glycine (2-MNG) as exhibiting the most favorable balance between the impact on water footprint, skin penetration potential and performance. The effectiveness of 2-MNG was confirmed by topical application on pigmented reconstructed epidermis and human skin explants. In addition, experiments have shown that unlike most melanogenesis inhibitors on the market, this molecule is not a tyrosinase inhibitor. 2-MNG binds to certain melanin precursors, preventing their integration into growing melanin and leading to inhibition of eumelanin and pheomelanin synthesis, without compromising the integrity of melanocytes.
{"title":"2-Mercaptonicotinoyl glycine, a new potent melanogenesis inhibitor, exhibits a unique mode of action while preserving melanocyte integrity","authors":"Peggy Sextius, Emilie Warrick, Amélie Prévot-Guéguiniat, Guillaume Lereaux, Florence Boirre, Ludwig Baux, Safa Ben Hassine, Jie Qiu, Xiaoming Huang, Jinzhu Xu, Sébastien Grégoire, Shosuke Ito, Kazumasa Wakamatsu, Xavier Marat","doi":"10.1111/pcmr.13168","DOIUrl":"10.1111/pcmr.13168","url":null,"abstract":"<p>Research on new ingredients that can prevent excessive melanin production in the skin while considering efficacy, safety but also environmental impact is of great importance to significantly improve the profile of existing actives on the market and avoid undesirable side effects. Here, the discovery of an innovative technology for the management of hyperpigmentation is described. High-throughput screening tests on a wide chemical diversity of molecules and in silico predictive methodologies were essential to design an original thiopyridinone backbone and select 2-mercaptonicotinoyl glycine (2-MNG) as exhibiting the most favorable balance between the impact on water footprint, skin penetration potential and performance. The effectiveness of 2-MNG was confirmed by topical application on pigmented reconstructed epidermis and human skin explants. In addition, experiments have shown that unlike most melanogenesis inhibitors on the market, this molecule is not a tyrosinase inhibitor. 2-MNG binds to certain melanin precursors, preventing their integration into growing melanin and leading to inhibition of eumelanin and pheomelanin synthesis, without compromising the integrity of melanocytes.</p>","PeriodicalId":219,"journal":{"name":"Pigment Cell & Melanoma Research","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/pcmr.13168","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140334133","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Stephan Forchhammer, Valentin Aebischer, Daniela Lenders, Christian M. Seitz, Christopher Schroeder, Alexandra Liebmann, Michael Abele, Hannah Wild, Ewa Bien, Malgorzata Krawczyk, Dominik T. Schneider, Ines B. Brecht, Lukas Flatz, Matthias Hahn
Pediatric melanomas are rare tumors that have clinical and histological differences from adult melanomas. In adult melanoma, the immunohistochemical marker PRAME is increasingly employed as a diagnostic adjunct. PRAME is also under investigation as a target structure for next-generation immunotherapies including T-cell engagers. Little is known about the characteristics of PRAME expression in pediatric melanoma. In this retrospective study, samples from 25 pediatric melanomas were compared with control groups of melanomas in young adults (18–30 years; n = 32), adult melanoma (>30 years, n = 30), and benign melanocytic nevi in children (0–18 years; n = 30) with regard to the immunohistochemical expression of PRAME (diffuse PRAME expression >75%/absolute expression). Pediatric melanomas show lower diffuse PRAME expression (4%) and lower absolute PRAME expression (25%) compared to young adult melanomas (15.6%/46.8%) and adult melanomas (50%/70%). A significant age-dependent expression could be observed. An analysis of event-free survival shows no prognostic role for PRAME in pediatric melanoma and young adult melanoma, but a significant association with diffuse PRAME expression in adulthood. The age dependency of PRAME expression poses a potential pitfall in the diagnostic application of melanocytic tumors in young patients and may limit therapeutic options within this age group. The immunohistochemical expression of the tumor-associated antigen PRAME is an increasingly important diagnostic marker for melanocytic tumors and is gaining attention as a possible immunotherapeutic target in melanoma. As the available data primarily stem from adult melanoma, and given the clinical and histological distinctions in pediatric melanomas, our understanding of PRAME expression in this specific patient group remains limited. The age-dependent low PRAME expression shown here constrains the use of this marker in pediatric melanoma and may also limit the use of immunotherapeutic strategies against PRAME in young patients.
{"title":"Characterization of PRAME immunohistochemistry reveals lower expression in pediatric melanoma compared to adult melanoma","authors":"Stephan Forchhammer, Valentin Aebischer, Daniela Lenders, Christian M. Seitz, Christopher Schroeder, Alexandra Liebmann, Michael Abele, Hannah Wild, Ewa Bien, Malgorzata Krawczyk, Dominik T. Schneider, Ines B. Brecht, Lukas Flatz, Matthias Hahn","doi":"10.1111/pcmr.13167","DOIUrl":"10.1111/pcmr.13167","url":null,"abstract":"<p>Pediatric melanomas are rare tumors that have clinical and histological differences from adult melanomas. In adult melanoma, the immunohistochemical marker PRAME is increasingly employed as a diagnostic adjunct. PRAME is also under investigation as a target structure for next-generation immunotherapies including T-cell engagers. Little is known about the characteristics of PRAME expression in pediatric melanoma. In this retrospective study, samples from 25 pediatric melanomas were compared with control groups of melanomas in young adults (18–30 years; <i>n</i> = 32), adult melanoma (>30 years, <i>n</i> = 30), and benign melanocytic nevi in children (0–18 years; <i>n</i> = 30) with regard to the immunohistochemical expression of PRAME (diffuse PRAME expression >75%/absolute expression). Pediatric melanomas show lower diffuse PRAME expression (4%) and lower absolute PRAME expression (25%) compared to young adult melanomas (15.6%/46.8%) and adult melanomas (50%/70%). A significant age-dependent expression could be observed. An analysis of event-free survival shows no prognostic role for PRAME in pediatric melanoma and young adult melanoma, but a significant association with diffuse PRAME expression in adulthood. The age dependency of PRAME expression poses a potential pitfall in the diagnostic application of melanocytic tumors in young patients and may limit therapeutic options within this age group. The immunohistochemical expression of the tumor-associated antigen PRAME is an increasingly important diagnostic marker for melanocytic tumors and is gaining attention as a possible immunotherapeutic target in melanoma. As the available data primarily stem from adult melanoma, and given the clinical and histological distinctions in pediatric melanomas, our understanding of PRAME expression in this specific patient group remains limited. The age-dependent low PRAME expression shown here constrains the use of this marker in pediatric melanoma and may also limit the use of immunotherapeutic strategies against PRAME in young patients.</p>","PeriodicalId":219,"journal":{"name":"Pigment Cell & Melanoma Research","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/pcmr.13167","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140178797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Marelize Snyman, Rachel Elizabeth Walsdorf, Sophia Nicole Wix, Jennifer Gibson Gill
Melanin synthesis involves the successful coordination of metabolic pathways across multiple intracellular compartments including the melanosome, mitochondria, ER/Golgi, and cytoplasm. While pigment production offers a communal protection from UV damage, the process also requires anabolic and redox demands that must be carefully managed by melanocytes. In this report we provide an updated review on melanin metabolism, including recent data leveraging new techniques, and technologies in the field of metabolism. We also discuss the many aspects of melanin synthesis that intersect with metabolic pathways known to impact melanoma phenotypes and behavior. By reviewing the metabolism of melanin synthesis, we hope to highlight outstanding questions and opportunities for future research that could improve patient outcomes in pigmentary and oncologic disease settings.
{"title":"The metabolism of melanin synthesis—From melanocytes to melanoma","authors":"Marelize Snyman, Rachel Elizabeth Walsdorf, Sophia Nicole Wix, Jennifer Gibson Gill","doi":"10.1111/pcmr.13165","DOIUrl":"10.1111/pcmr.13165","url":null,"abstract":"<p>Melanin synthesis involves the successful coordination of metabolic pathways across multiple intracellular compartments including the melanosome, mitochondria, ER/Golgi, and cytoplasm. While pigment production offers a communal protection from UV damage, the process also requires anabolic and redox demands that must be carefully managed by melanocytes. In this report we provide an updated review on melanin metabolism, including recent data leveraging new techniques, and technologies in the field of metabolism. We also discuss the many aspects of melanin synthesis that intersect with metabolic pathways known to impact melanoma phenotypes and behavior. By reviewing the metabolism of melanin synthesis, we hope to highlight outstanding questions and opportunities for future research that could improve patient outcomes in pigmentary and oncologic disease settings.</p>","PeriodicalId":219,"journal":{"name":"Pigment Cell & Melanoma Research","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/pcmr.13165","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140038400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tietz albinism-deafness syndrome (TADS) is a rare and severe manifestation of Waardenburg syndrome that is primarily linked to mutations in MITF. In this report, we present a case of TADS resulting from a novel c.637G>C mutation in MITF (p.Glu213Gln; GenBank Accession number: NM_000248). A 3-year-old girl presented with congenital generalized hypopigmentation of the hair, skin, and irides along with complete sensorineural hearing loss. Histopathological and electron microscopy investigations indicated that this variant did not alter the number of melanocytes in the skin but significantly impaired melanosome maturation within melanocytes. Comprehensive melanin analysis revealed marked reductions in both eumelanin (EM) and pheomelanin (PM) rather than changes in the EM-to-PM ratio observed in oculocutaneous albinism. We conducted an electrophoretic mobility shift assay to investigate the binding capability of the identified variant to DNA sequences containing the E-box motif along with other known variants (p.Arg217del and p.Glu213Asp). Remarkably, all three variants exhibited dominant-negative effects, thus providing novel insights into the pathogenesis of TADS. This study sheds light on the genetic mechanisms underlying TADS and offers a deeper understanding of this rare condition and its associated mutations in MITF.
{"title":"Genetic insights into Tietz albinism-deafness syndrome: A new dominant-negative mutation in MITF","authors":"Kohei Yamamoto, Ken Okamura, Kazumasa Wakamatsu, Shosuke Ito, Kozue Akabane, Yosuke Arai, Junnosuke Kawaguchi, Yutaka Hozumi, Tamio Suzuki","doi":"10.1111/pcmr.13166","DOIUrl":"10.1111/pcmr.13166","url":null,"abstract":"<p>Tietz albinism-deafness syndrome (TADS) is a rare and severe manifestation of Waardenburg syndrome that is primarily linked to mutations in <i>MITF</i>. In this report, we present a case of TADS resulting from a novel c.637G>C mutation in <i>MITF</i> (p.Glu213Gln; GenBank Accession number: NM_000248). A 3-year-old girl presented with congenital generalized hypopigmentation of the hair, skin, and irides along with complete sensorineural hearing loss. Histopathological and electron microscopy investigations indicated that this variant did not alter the number of melanocytes in the skin but significantly impaired melanosome maturation within melanocytes. Comprehensive melanin analysis revealed marked reductions in both eumelanin (EM) and pheomelanin (PM) rather than changes in the EM-to-PM ratio observed in oculocutaneous albinism. We conducted an electrophoretic mobility shift assay to investigate the binding capability of the identified variant to DNA sequences containing the E-box motif along with other known variants (p.Arg217del and p.Glu213Asp). Remarkably, all three variants exhibited dominant-negative effects, thus providing novel insights into the pathogenesis of TADS. This study sheds light on the genetic mechanisms underlying TADS and offers a deeper understanding of this rare condition and its associated mutations in <i>MITF</i>.</p>","PeriodicalId":219,"journal":{"name":"Pigment Cell & Melanoma Research","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140027017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ahmed Ahmed Touni, Rachel Sohn, Cormac Cosgrove, Rohan S. Shivde, Emilia R. Dellacecca, Rasha T. A. Abdel-Aziz, Kettil Cedercreutz, Stefan J. Green, Hossam Abdel-Wahab, I. Caroline Le Poole
Oral neomycin administration impacts the gut microbiome and delays vitiligo development in mice, and topical antibiotics may likewise allow the microbiome to preserve skin health and delay depigmentation. Here, we examined the effects of 6-week topical antibiotic treatment on vitiligo-prone pmel-1 mice. Bacitracin, Neosporin, or Vaseline were applied to one denuded flank, while the contralateral flank was treated with Vaseline in all mice. Ventral depigmentation was quantified weekly. We found that topical Neosporin treatment significantly reduced depigmentation and exhibited effects beyond the treated area, while Bacitracin ointment had no effect. Stool samples collected from four representative mice/group during treatment revealed that Neosporin treatment aligned with reduced abundance of the Alistipes genus in the gut, while relevant changes to the skin microbiome at end point were less apparent. Either antibiotic treatment led to reduced expression of MR1, potentially limiting mucosal-associated invariant T-cell activation, while Neosporin-treated skin selectively revealed significantly reduced CD8+ T-cell abundance. The latter finding aligned with reduced expression of multiple inflammatory markers and markedly increased regulatory T-cell density. Our studies on favorable skin and oral antibiotic treatment share the neomycin compound, and in either case, microbial changes were most apparent in stool samples. Taken together, neomycin-containing antibiotic applications can mediate skin Treg infiltration to limit vitiligo development. Our study highlights the therapeutic potential of short-term antibiotic applications to limit depigmentation vitiligo.
口服新霉素会影响小鼠的肠道微生物群并延缓白癜风的发展,而局部使用抗生素同样可以使微生物群保持皮肤健康并延缓脱色。在这里,我们研究了对易患白癜风的 pmel-1 小鼠进行 6 周局部抗生素治疗的效果。将杆菌肽、新孢子菌素或凡士林涂抹在一只脱色小鼠的侧腹上,同时用凡士林处理所有小鼠的对侧侧腹。每周对腹侧色素沉着进行量化。我们发现,局部新孢子菌素治疗可显著减少色素沉着,并在治疗区域外显示出效果,而百雀羚软膏则没有效果。在治疗过程中,从每组四只具有代表性的小鼠身上采集的粪便样本显示,新孢子菌治疗与肠道中Alistipes属丰度的降低相一致,而皮肤微生物组在终点时的相关变化则不太明显。任何一种抗生素治疗都会导致MR1表达减少,从而可能限制粘膜相关不变T细胞的活化,而新孢子菌素处理过的皮肤则选择性地显示CD8+ T细胞丰度显著降低。后一项发现与多种炎症标志物表达减少和调节性 T 细胞密度明显增加相一致。我们对良好皮肤和口服抗生素治疗的研究都使用了新霉素化合物,在这两种情况下,粪便样本中的微生物变化都最为明显。综上所述,应用含新霉素的抗生素可以介导皮肤Treg浸润,从而限制白癜风的发展。我们的研究强调了短期应用抗生素限制脱色性白癜风的治疗潜力。
{"title":"Topical antibiotics limit depigmentation in a mouse model of vitiligo","authors":"Ahmed Ahmed Touni, Rachel Sohn, Cormac Cosgrove, Rohan S. Shivde, Emilia R. Dellacecca, Rasha T. A. Abdel-Aziz, Kettil Cedercreutz, Stefan J. Green, Hossam Abdel-Wahab, I. Caroline Le Poole","doi":"10.1111/pcmr.13164","DOIUrl":"10.1111/pcmr.13164","url":null,"abstract":"<p>Oral neomycin administration impacts the gut microbiome and delays vitiligo development in mice, and topical antibiotics may likewise allow the microbiome to preserve skin health and delay depigmentation. Here, we examined the effects of 6-week topical antibiotic treatment on vitiligo-prone pmel-1 mice. Bacitracin, Neosporin, or Vaseline were applied to one denuded flank, while the contralateral flank was treated with Vaseline in all mice. Ventral depigmentation was quantified weekly. We found that topical Neosporin treatment significantly reduced depigmentation and exhibited effects beyond the treated area, while Bacitracin ointment had no effect. Stool samples collected from four representative mice/group during treatment revealed that Neosporin treatment aligned with reduced abundance of the <i>Alistipes</i> genus in the gut, while relevant changes to the skin microbiome at end point were less apparent. Either antibiotic treatment led to reduced expression of MR1, potentially limiting mucosal-associated invariant T-cell activation, while Neosporin-treated skin selectively revealed significantly reduced CD8+ T-cell abundance. The latter finding aligned with reduced expression of multiple inflammatory markers and markedly increased regulatory T-cell density. Our studies on favorable skin and oral antibiotic treatment share the neomycin compound, and in either case, microbial changes were most apparent in stool samples. Taken together, neomycin-containing antibiotic applications can mediate skin Treg infiltration to limit vitiligo development. Our study highlights the therapeutic potential of short-term antibiotic applications to limit depigmentation vitiligo.</p>","PeriodicalId":219,"journal":{"name":"Pigment Cell & Melanoma Research","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/pcmr.13164","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140027018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xiao-lian Liu, Zhou Run-hua, Jing-xuan Pan, Zhi-jie Li, Le Yu, Yi-lei Li
Uveal melanoma (UM) is the most common primary malignant intraocular tumor in adults. Although primary UM can be effectively controlled, a significant proportion of cases (40% or more) eventually develop distant metastases, commonly in the liver. Metastatic UM remains a lethal disease with limited treatment options. The initiation of UM is typically attributed to activating mutations in GNAQ or GNA11. The elucidation of the downstream pathways such as PKC/MAPK, PI3K/AKT/mTOR, and Hippo-YAP have provided potential therapeutic targets. Concurrent mutations in BRCA1 associated protein 1 (BAP1) or splicing factor 3b subunit 1 (SF3B1) are considered crucial for the acquisition of malignant potential. Furthermore, in preclinical studies, actionable targets associated with BAP1 loss or oncogenic mutant SF3B1 have been identified, offering promising avenues for UM treatment. This review aims to summarize the emerging targeted and epigenetic therapeutic strategies for metastatic UM carrying specific driver mutations and the potential of combining these approaches with immunotherapy, with particular focus on those in upcoming or ongoing clinical trials.
葡萄膜黑色素瘤(UM)是成人最常见的原发性眼内恶性肿瘤。虽然原发性 UM 可以得到有效控制,但很大一部分病例(40% 或更多)最终会发生远处转移,常见于肝脏。转移性 UM 仍是一种致命疾病,治疗方案有限。UM 的发生通常归因于 GNAQ 或 GNA11 的激活突变。对 PKC/MAPK、PI3K/AKT/mTOR 和 Hippo-YAP 等下游通路的阐明提供了潜在的治疗靶点。BRCA1 相关蛋白 1(BAP1)或剪接因子 3b 亚基 1(SF3B1)的并发突变被认为是获得恶性潜能的关键。此外,在临床前研究中,已经发现了与 BAP1 缺失或致癌突变 SF3B1 相关的可操作靶点,为 UM 治疗提供了有希望的途径。本综述旨在总结针对携带特定驱动基因突变的转移性 UM 的新兴靶向和表观遗传学治疗策略,以及将这些方法与免疫疗法相结合的潜力,并特别关注那些即将或正在进行的临床试验。
{"title":"Emerging therapeutic strategies for metastatic uveal melanoma: Targeting driver mutations","authors":"Xiao-lian Liu, Zhou Run-hua, Jing-xuan Pan, Zhi-jie Li, Le Yu, Yi-lei Li","doi":"10.1111/pcmr.13161","DOIUrl":"10.1111/pcmr.13161","url":null,"abstract":"<p>Uveal melanoma (UM) is the most common primary malignant intraocular tumor in adults. Although primary UM can be effectively controlled, a significant proportion of cases (40% or more) eventually develop distant metastases, commonly in the liver. Metastatic UM remains a lethal disease with limited treatment options. The initiation of UM is typically attributed to activating mutations in <i>GNAQ</i> or <i>GNA11</i>. The elucidation of the downstream pathways such as PKC/MAPK, PI3K/AKT/mTOR, and Hippo-YAP have provided potential therapeutic targets. Concurrent mutations in BRCA1 associated protein 1 (<i>BAP1</i>) or splicing factor 3b subunit 1 (<i>SF3B1</i>) are considered crucial for the acquisition of malignant potential. Furthermore, in preclinical studies, actionable targets associated with BAP1 loss or oncogenic mutant SF3B1 have been identified, offering promising avenues for UM treatment. This review aims to summarize the emerging targeted and epigenetic therapeutic strategies for metastatic UM carrying specific driver mutations and the potential of combining these approaches with immunotherapy, with particular focus on those in upcoming or ongoing clinical trials.</p>","PeriodicalId":219,"journal":{"name":"Pigment Cell & Melanoma Research","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/pcmr.13161","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139970333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ying Wang, Emilee Herringshaw, R. Rox Anderson, Joshua Tam
Post-inflammatory hyperpigmentation (PIH) is a hypermelanosis that often occurs secondary to skin irritation or injury, especially in darker skin tones, for which there is currently a lack of effective treatment options. Few preclinical models are available to study PIH. Here, we show that the Yucatan miniature pig consistently develops PIH after skin injuries. Skin wounds were produced on Yucatan pigs by needle punches, full-thickness excisions, or burns. Wound sites were monitored and photographed regularly. Tissue samples were collected after 24 weeks and processed for histology/immunohistochemistry. Skin pigmentation and histologic changes were quantified by computer-assisted image analyses. All injury methods resulted in hyperpigmentation. Melanin content at the histologic level was quantified in the larger (burn and excision) wounds, showing a significant increase compared to uninjured skin. Increased melanin was found for both epidermal and dermal regions. Dermal melanin deposits were primarily clustered around the papillary vasculature, and were associated not with melanocytes but with leukocytes. The Yucatan miniature pig model recapitulates key clinical and histologic features of PIH in humans, including skin hyperpigmentation at both gross and histologic levels, and persistence of dermal melanin subsequent to injury. This model could be used to further our understanding of the etiology of PIH, and for new therapy development.
{"title":"The Yucatan miniature swine as a model for post-inflammatory hyperpigmentation","authors":"Ying Wang, Emilee Herringshaw, R. Rox Anderson, Joshua Tam","doi":"10.1111/pcmr.13162","DOIUrl":"10.1111/pcmr.13162","url":null,"abstract":"<p>Post-inflammatory hyperpigmentation (PIH) is a hypermelanosis that often occurs secondary to skin irritation or injury, especially in darker skin tones, for which there is currently a lack of effective treatment options. Few preclinical models are available to study PIH. Here, we show that the Yucatan miniature pig consistently develops PIH after skin injuries. Skin wounds were produced on Yucatan pigs by needle punches, full-thickness excisions, or burns. Wound sites were monitored and photographed regularly. Tissue samples were collected after 24 weeks and processed for histology/immunohistochemistry. Skin pigmentation and histologic changes were quantified by computer-assisted image analyses. All injury methods resulted in hyperpigmentation. Melanin content at the histologic level was quantified in the larger (burn and excision) wounds, showing a significant increase compared to uninjured skin. Increased melanin was found for both epidermal and dermal regions. Dermal melanin deposits were primarily clustered around the papillary vasculature, and were associated not with melanocytes but with leukocytes. The Yucatan miniature pig model recapitulates key clinical and histologic features of PIH in humans, including skin hyperpigmentation at both gross and histologic levels, and persistence of dermal melanin subsequent to injury. This model could be used to further our understanding of the etiology of PIH, and for new therapy development.</p>","PeriodicalId":219,"journal":{"name":"Pigment Cell & Melanoma Research","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139739988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Melanocytic nevi (skin moles) have been regarded as a valuable example of cell senescence occurring in vivo. However, a study of induced nevi in a mouse model reported that the nevi were arrested by cell interactions rather than a cell-autonomous process like senescence, and that size distributions of cell nests within nevi could not be accounted for by a stochastic model of oncogene-induced senescence. Moreover, others reported that some molecular markers used to identify cell senescence in human nevi are also found in melanoma cells—not senescent. It has thus been questioned whether nevi really are senescent, with potential implications for melanoma diagnosis and therapy. Here I review these areas, along with the genetic, biological, and molecular evidence supporting senescence in nevi. In conclusion, there is strong evidence that cells of acquired human benign (banal) nevi are very largely senescent, though some must contain a minor non-senescent cell subpopulation. There is also persuasive evidence that this senescence is primarily induced by dysfunctional telomeres rather than directly oncogene-induced.
{"title":"Review: Are moles senescent?","authors":"Dorothy C. Bennett","doi":"10.1111/pcmr.13163","DOIUrl":"10.1111/pcmr.13163","url":null,"abstract":"<p>Melanocytic nevi (skin moles) have been regarded as a valuable example of cell senescence occurring in vivo. However, a study of induced nevi in a mouse model reported that the nevi were arrested by cell interactions rather than a cell-autonomous process like senescence, and that size distributions of cell nests within nevi could not be accounted for by a stochastic model of oncogene-induced senescence. Moreover, others reported that some molecular markers used to identify cell senescence in human nevi are also found in melanoma cells—not senescent. It has thus been questioned whether nevi really are senescent, with potential implications for melanoma diagnosis and therapy. Here I review these areas, along with the genetic, biological, and molecular evidence supporting senescence in nevi. In conclusion, there is strong evidence that cells of acquired human benign (banal) nevi are very largely senescent, though some must contain a minor non-senescent cell subpopulation. There is also persuasive evidence that this senescence is primarily induced by dysfunctional telomeres rather than directly oncogene-induced.</p>","PeriodicalId":219,"journal":{"name":"Pigment Cell & Melanoma Research","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/pcmr.13163","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139739987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nathaniel B. Goldstein, Andrea Steel, Landon Tomb, Zachary Berk, Junxiao Hu, Velmurugan Balaya, Laura Hoaglin, Kavya Ganuthula, Meet Patel, Erica Mbika, William A. Robinson, Dennis R. Roop, David A. Norris, Stanca A. Birlea
We have discovered that human vitiligo patients treated with narrow-band UVB (NBUVB) demonstrated localized resistance to repigmentation in skin sites characterized by distinct cellular and molecular pathways. Using immunostaining studies, discovery-stage RNA-Seq analysis, and confirmatory in situ hybridization, we analyzed paired biopsies collected from vitiligo lesions that did not repigment after 6 months of NBUVB treatment (non-responding) and compared them with repigmented (responding) lesions from the same patient. Non-responding lesions exhibited acanthotic epidermis, had low number of total, proliferative, and differentiated melanocyte (MC) populations, and increased number of senescent keratinocytes (KCs) and of cytotoxic CD8+ T cells as compared with responding lesions. The abnormal response in the non-responding lesions was driven by a dysregulated cAMP pathway and of upstream activator PDE4B, and of WNT/β-catenin repigmentation pathway. Vitiligo-responding lesions expressed high levels of WNT10B ligand, a molecule that may prevent epidermal senescence induced by NBUVB, and that in cultured melanoblasts prevented the pro-melanogenic effect of α-MSH. Understanding the pathways that govern lack of NBUVB-induced vitiligo repigmentation has a great promise in guiding the development of new therapeutic strategies for vitiligo.
{"title":"Vitiligo non-responding lesions to narrow band UVB have intriguing cellular and molecular abnormalities that may prevent epidermal repigmentation","authors":"Nathaniel B. Goldstein, Andrea Steel, Landon Tomb, Zachary Berk, Junxiao Hu, Velmurugan Balaya, Laura Hoaglin, Kavya Ganuthula, Meet Patel, Erica Mbika, William A. Robinson, Dennis R. Roop, David A. Norris, Stanca A. Birlea","doi":"10.1111/pcmr.13160","DOIUrl":"10.1111/pcmr.13160","url":null,"abstract":"<p>We have discovered that human vitiligo patients treated with narrow-band UVB (NBUVB) demonstrated localized resistance to repigmentation in skin sites characterized by distinct cellular and molecular pathways. Using immunostaining studies, discovery-stage RNA-Seq analysis, and confirmatory in situ hybridization, we analyzed paired biopsies collected from vitiligo lesions that did not repigment after 6 months of NBUVB treatment (non-responding) and compared them with repigmented (responding) lesions from the same patient. Non-responding lesions exhibited acanthotic epidermis, had low number of total, proliferative, and differentiated melanocyte (MC) populations, and increased number of senescent keratinocytes (KCs) and of cytotoxic CD8+ T cells as compared with responding lesions. The abnormal response in the non-responding lesions was driven by a dysregulated cAMP pathway and of upstream activator PDE4B, and of WNT/β-catenin repigmentation pathway. Vitiligo-responding lesions expressed high levels of WNT10B ligand, a molecule that may prevent epidermal senescence induced by NBUVB, and that in cultured melanoblasts prevented the pro-melanogenic effect of α-MSH. Understanding the pathways that govern lack of NBUVB-induced vitiligo repigmentation has a great promise in guiding the development of new therapeutic strategies for vitiligo.</p>","PeriodicalId":219,"journal":{"name":"Pigment Cell & Melanoma Research","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139720936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The 20th International Congress of the Society for Melanoma Research","authors":"","doi":"10.1111/pcmr.13152","DOIUrl":"10.1111/pcmr.13152","url":null,"abstract":"","PeriodicalId":219,"journal":{"name":"Pigment Cell & Melanoma Research","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139424167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}